Cellular therapies, such as stem cell therapies, offer enormous hope for treating illnesses, diseases and tissue defects. A significant barrier for the effective implementation of cell therapies is the inability to target a large quantity of viable cells to tissues of interest with high efficiency. Systemic infusion is generally desired, because it minimizes the invasiveness of cell therapy and maximizes practical aspects of repeated doses. It also permits the cells to mimic natural cell trafficking processes and helps to ensure that cells remain in close proximity to oxygen and nutrient-rich blood vessels. However, cells generally exhibit poor homing capability or lose their capacity to home following ex vivo culture expansion.
For example, many pre-clinical studies suggest that mesenchymal stem cells (MSCs) have a beneficial effect on left ventricular (LV) remodeling and the recovery of cardiac performance following myocardial infarction (MI). As such, one would expect that it would be beneficial to treat MI by systemically infusing a patient with high concentrations of MSCs, such as autologous or allogeneic MSCs expanded in ex vivo culture. However, studies show that less than 1% of MSCs expanded in ex vivo culture typically reach the ischemic myocardium after systemic injection. This inefficiency in MSC homing is a consequence of various factors, but is primarily attributed to an absence of relevant cell surface homing ligands such as CXC chemokine receptor 4 (CXCR4). CXCR4 is a chemotactic receptor that recognizes the chemokine stromal-derived factor-1 (SDF-1), which is up-regulated in the ischemic myocardium after infarction and is believed to play a crucial role in cardiac recovery by recruiting CXCR4+ MSCs toward the SDF-1 gradient. Culture-expanded MSCs develop heterogeneous receptor expression and appear to lose key homing ligands, such as CXCR4, during cell culture, which contributes to the inefficiency of MSC homing in vivo. As most of the transplanted MSCs rapidly decline following IV infusion, there is a significant need to improve homing efficiency following systemic administration.
The culture expansion of MSCs for autologous administration takes several weeks to obtain the necessary number of MSCs needed for regenerative therapy, thus complicating the administration of MSC therapy in patients with an acute MI (AMI), who have a small therapeutic window. The cultivation of MSCs under hypoxia, treating MSCs with a cytokine cocktail, and virus-mediated CXCR4 transduction have all been shown to induce expression of CXCR4 on the surface of MSCs more quickly, but each of these approaches requires over 24 hours of MSC culture to induce CXCR4 expression. In turn, this may lead to significant changes in the properties of the MSCs. The key limitations in all of these approaches are the long-term processing time (>24 hours) to up-regulate CXCR4, the number of complicated steps, and the requirement for invasiveness to transfect DNA or to transduce a virus particle.
Because 1) the CXCR4/SDF-1 axis plays an important role in MSC homing to the ischemic myocardium, 2) SDF-1 is highly expressed up to 48 hours after infarction, and 3) the therapeutic window to treat patients with acute MI is small, the current approaches to induce CXCR4 expression, all of which require long-term MSC culture, are unlikely to be useful in a clinical setting. Therefore, a novel method to introduce CXCR4 on the surface of MSCs quickly (within an hour or less) is required for the allograft administration of MSCs to be a viable treatment for patients with an acute MI.
The surface modification of living cells with natural and synthetic polymers promises new opportunities in this arena. Recently, a variety of functional groups and bioactive substances have been introduced to the surface of various cell types. Methods employed in cell surface modification include covalent conjugation, hydrophobic interaction, and electrostatic interaction. Cell surface modifications, however, often cause severe cytotoxicity, or compromise the normal function of the cell. As such, it would be advantageous to develop new compositions and methods for quickly and efficiently modifying the surface of therapeutically important cell types, such as MSCs, with an appropriate targeting moiety without causing severe cytotoxicity and/or compromising the normal functioning of the cell.